Back to Search
Start Over
The Pyrin Inflammasome in Health and Disease
- Source :
- Frontiers in Immunology, Vol 10 (2019), Frontiers in Immunology
- Publication Year :
- 2019
- Publisher :
- Frontiers Media SA, 2019.
-
Abstract
- The pyrin inflammasome has evolved as an innate immune sensor to detect bacterial toxin-induced Rho guanosine triphosphatase (Rho GTPase)-inactivation, a process that is similar to the “guard” mechanism in plants. Rho GTPases act as molecular switches to regulate a variety of signal transduction pathways including cytoskeletal organization. Pathogens can modulate Rho GTPase activity to suppress host immune responses such as phagocytosis. Pyrin is encoded by MEFV, the gene that is mutated in patients with familial Mediterranean fever (FMF). FMF is the prototypic autoinflammatory disease characterized by recurring short episodes of systemic inflammation and is a common disorder in many populations in the Mediterranean basin. Pyrin specifically senses modifications in the activity of the small GTPase RhoA, which binds to many effector proteins including the serine/threonine-protein kinases PKN1 and PKN2 and actin-binding proteins. RhoA activation leads to PKN-mediated phosphorylation-dependent pyrin inhibition. Conversely, pathogen virulence factors downregulate RhoA activity in a variety of ways, and these changes are detected by the pyrin inflammasome irrespective of the type of modifications. MEFV pathogenic variants favor the active state of pyrin and elicit proinflammatory cytokine release and pyroptosis. They can be inherited either as a dominant or recessive trait depending on the variant's location and effect on the protein function. Mutations in the C-terminal B30.2 domain are usually considered recessive, although heterozygotes may manifest a biochemical or even a clinical phenotype. These variants are hypomorphic in regard to their effect on intramolecular interactions, but ultimately accentuate pyrin activity. Heterozygous mutations in other domains of pyrin affect residues critical for inhibition or protein oligomerization, and lead to constitutively active inflammasome. In healthy carriers of FMF mutations who have the subclinical inflammatory phenotype, the increased activity of pyrin might have been protective against endemic infections over human history. This finding is supported by the observation of high carrier frequencies of FMF-mutations in multiple populations. The pyrin inflammasome also plays a role in mediating inflammation in other autoinflammatory diseases linked to dysregulation in the actin polymerization pathway. Therefore, the assembly of the pyrin inflammasome is initiated in response to fluctuations in cytoplasmic homeostasis and perturbations in cytoskeletal dynamics.
- Subjects :
- lcsh:Immunologic diseases. Allergy
0301 basic medicine
RHOA
Inflammasomes
Immunology
Familial Mediterranean fever
Review
GTPase
Pyrin domain
03 medical and health sciences
RhoA GTPases
Yersinia toxins
0302 clinical medicine
familial Mediterranean fever
medicine
Animals
Humans
Immunology and Allergy
Protein oligomerization
biology
Pyroptosis
Inflammasome
Pyrin
autoinflammatory diseases
serine-threonine kinase
medicine.disease
MEFV
Immunity, Innate
Cell biology
030104 developmental biology
biology.protein
pyrin inflammasome
lcsh:RC581-607
030215 immunology
medicine.drug
Subjects
Details
- ISSN :
- 16643224
- Volume :
- 10
- Database :
- OpenAIRE
- Journal :
- Frontiers in Immunology
- Accession number :
- edsair.doi.dedup.....a19c091717c3ac725de1bcd69217bacc
- Full Text :
- https://doi.org/10.3389/fimmu.2019.01745